46 Anti-tumour immune responses in melanoma brain metastases require cDC1 population and the extracranial tumour

Vollständiger Abstract

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Abstract Introduction Brain metastases (BrM) are associated with poor prognosis, partially due to the specialized immune-microenvironment in the brain. Our previous study demonstrated that intracranial tumours alone are poorly immunogenic, but simultaneous presence of a subcutaneous tumour, mimicking the extracranial disease observed in patients, greatly enhances immune checkpoint blockade efficacy. Here we aim to elucidate the role of conventional dendritic cells type 1 (cDC1) in anti-tumour immune responses in BrM and their dependence on the systemic anti-tumour immunity generated by extracranial tumour. Method Luciferase-tagged B16-Ova melanoma cells were injected intracranially into C57Bl/6 mice with or without subcutaneous tumours. Intracranial tumour burden was measured by bioluminescence imaging in constitutive and conditional cDC1 deletion models. Intra-tumoral immune cells were analysed by spectral flow-cytometry. Results A significantly lower intracranial tumour burden was observed in the presence of cDC1s in mice with extracranial tumours, while in the absence of extracranial tumours cDC1 presence induced only a tendency towards reduced intracranial tumour burden. The simultaneous presence of extracranial tumour and cDC1s was associated with significantly higher abundance of natural killer and effector CD8+ T cells in intracranial tumours as compared to mice lacking cDC1s and/or extracranial tumour. Moreover, the presence of extracranial tumour increased the expression of activation markers in intracranial cDC1s, and the abundance of cDC1s and “mature DCs enriched in immunoregulatory molecules” in intracranial tumours. Conclusions Our data suggest that extracranial and intracranial cDC1 pools are both required for an efficient control of intracranial tumour growth. We hypothesize that extracranial tumour inhibits intracranial tumour growth through extracranial cDC1-mediated priming and expansion of CD8+ T cells which then home to intracranial tumours, by directly enhancing the activation of intracranial cDC1s, or a combination of both